Pharmaceutical composition of a pde4 or pde 3/4 inhibitor and histamine receptor antagonist

ABSTRACT

The invention relates to the combined administration of PDE4 or PDE3/4 inhibitors and histamine receptor antagonists for the treatment of respiratory diseases.

FIELD OF APPLICATION OF THE INVENTION

The present invention relates to combinations of pharmaceutically activesubstances for use in the treatment of respiratory diseases.

The substances used in the combinations according to the invention areknown active compounds from the PDE4 and PDE3/4 inhibitors class andactive compounds from the class of the histamine receptor antagonists.

KNOWN TECHNICAL BACKGROUND

In the international application WO03/000289 compositions are describedwhich comprise a PDE4 inhibitor and a H1-receptor antagonist and the useof these compositions for the manufacture of a medicament for thetreatment of respiratory diseases.

DESCRIPTION OF THE INVENTION

Asthma is a common inflammatory disease of the respiratory tract,accounting for 1-3% of all office visits, 500,000 hospital admissionsper year and more pediatric hospital admissions than any other singleillness in the US. Annually, more than 5000 children and adults die ofasthma attacks in the United States (William E. S.; Goodmann GilmannA.:The pharmacological Basis of Therapeutics, 9^(th) Edition, pp. 152 &659-682, Mc Graw Hill, New York 1996).

Asthma can no longer be viewed simply as a reversible airwayobstruction. It should instead be considered primarily as aninflammatory illness that has bronchial hyperactivity and bronchospasmas its results. Allergen specific immunoglobulin E (IgE) is bound to themast cells via Fc receptors. It is a fragment obtained by papaindigestion of immunoglobulin molecules and contains most of the antigenicdeterminants. When an allergen comes into contact with IgE, the mastcells are activated and release a number of inflammatory mediators,which include granule contents like histamine, proteases, heparin, andtumor necrosis factor (TNF), a variety of lipid membrane derivedmolecules like prostaglandins, leukotrienes and platelet activatingfactor (PAF), and a number of cytokines like interleukin (IL)-1, 3, 4,5, 6 and 8 and chemokines. An enormous variety of mediators are releasedwhich have more than one potent effect on airway inflammation.

As a result of vasodilation, increased vasopermeability and increasedendothelial adhesiveness towards leukocytes further leads to an influxof inflammatory cells like lymphocytes, eosinophils and macrophages fromblood circulation into the tissues. This in turn leads to the release ofmediators which have further inflammatory effects (Rao A. R. et al.Recent Perspectives in the design of antiasthmatic agents, Pharmazie,55, 7, 475-482, 2000).

Thus, it can be understood that it is unlikely that drugs affecting asingle mediator can satisfactorily treat the disease alone. As asthma isone of the major diseases affecting mankind, there is a need to developdrugs which can affect a wide variety of mediators.

Therefore, it is the object of the present invention to make availablerespiratory tract therapeutics which fulfill the following conditions:

-   -   Favorable simultaneous influence on several of the inflammatory        mediators    -   Marked bronchorelaxation and -dilatation    -   Good oral availability    -   Minor side effects    -   Good suitability for long-term therapy    -   Favorable influence on bronchial hyperreactivity

It has now been found that the combined use of a PDE4 or a PDE3/4inhibitor and a histamine receptor antagonist outstandingly fulfills theabove-mentioned conditions.

The invention thus relates to the combined use of a PDE4 or a PDE3/4inhibitor and a histamine receptor antagonist in the treatment ofrespiratory diseases.

By the expression “PDE4 inhibitor” is meant a selectivephosphodiesterase inhibitor, which inhibits preferentially the type 4phosphodiesterase when compared to other known types ofphosphodiesterase, e.g. type 1, 2, 3, 5 etc., whereby the compound has alower IC₅₀ (more potent) for the type 4 phosphodiesterase, such as wherethe IC₅₀ for PDE4 inhibition is about factor 10 lower compared to IC₅₀for Inhibition of other known type of phosphodiesterase, e.g. type 1, 2,3, 5 etc.

Analogously, the expression “PDE3/4 inhibitor” is defined. Methods todetermine the activity and selectivity of a phosphodiesterase inhibitorare known to the person skilled in the art. In this connection it may bementioned, for example, the methods described by Thompson et al. (AdvCycl Nucl Res 10: 69-92, 1979), Glembycz et al. (Br J Pharmacol 118:1945-1958,1996) and the phosphodiesterase scintillation proximity assayof Amersham Pharmacia Biotech.

By the expression “histamine receptor antagonist” are meant H₁-receptorantagonists, particularly the so called H₁-receptor antagonists of thesecond generation (Mutschler, Arzneimittelwirkungen, 8. Edition, 2001,pages 456-461).

As possible PDE4 or PDE3/4 inhibitors within the meaning of the presentinvention may be mentioned, by way of example, those PDE4 or PDE3/4inhibitors which are named expressis verbis as an example, or describedor claimed generically in the following patent applications and patents:DE 1545687, DE 2028869, DE 2123328, DE 2315801, DE 2402908, DE 2413935,DE 3900233, EP 0103497, EP 0139464, EP 0158380, EP 0163965, EP 0335386,EP 0389282, EP 0393500, EP 0428302, EP 0435811, EP 0449216, EP 0459505,EP 0470805, EP 0490823, EP 0506194, EP 0510562, EP 0511865, EP 0527117,EP 0553174, EP 0557016, EP 0626939, EP 0664289, EP 0671389, EP 0685474,EP 0685475, EP 0685479, EP 0731099, EP 0736532, EP 0738715, EP 0748805,EP 0763534, EP 0816357, EP 0819688, EP 0819689, EP 0832886, EP 0834508,EP 0848000, JP 92234389, JP 94329652, JP 95010875, JP 98072415, JP98147585, U.S. Pat. Nos. 5,703,098, 5,739,144, WO 9117991, WO 9200968,WO 9212961, WO 9307146, WO 9315044, WO 9315045, WO 9318024, WO 9319068,WO 9319720, WO 9319747, WO 9319749, WO 9319751, WO 9325517, WO 9402465,WO 9412461, WO 9420455, WO 9422852, WO 9427947, WO 9500516, WO 9501338,WO 9501980, WO 9503794, WO 9504045, WO 9504046, WO 9505386, WO 9508534,WO 9509623, WO 9509624, WO 9509627, WO 9509836, WO 9514667, WO 9514680,WO 9514681, WO 9517392, WO 9517399, WO 9519362, WO 9520578, WO 9522520,WO 9524381, WO 9527692, WO 9535281, WO 9535283, WO 9535284, WO 9600218,WO 9601825, WO 9606843, WO 9603399, WO 9611690, WO 9611917, WO 9612720,WO 9631486, WO 9631487, WO 9635683, WO 9636595, WO 9636596, WO 9636611,WO 9636625, WO 9636626, WO 9636638, WO 9638150, WO 9639408, WO 9640636,WO 9703967, WO 9704779, WO 9705105, WO 9708143, WO 9709345, WO 9712895,WO 9718208, WO 9719078, WO 9720833, WO 9722585, WO 9722586, WO 9723457,WO 9723460, WO 9723461, WO 9724117, WO 9724355, WO 9725312, WO 9728131,WO 9730999, WO 9731000, WO 9732853, WO 9735854, WO 9736905, WO 9740032,WO 9743288, WO 9744036, WO 9744322, WO 9747604, WO 9748697, WO 9804534,WO 9805327, WO 9806692, WO 9806704, WO 9807715, WO 9808828, WO 9808830,WO 9808841, WO 9808844, WO 9809946, WO 9809961, WO 9811113, WO 9814448,WO 9818796, WO 9821207, WO 9821208, WO 9821209, WO 9822453, WO 9831674,WO 9840382, WO 9845268, WO 9855481, WO 9856756, WO 9905111, WO 9905112,WO 9505113, WO 9906404, WO 9918095, WO 9931071, WO 9931090, WO 9947505,WO 9957115, WO 9957118, WO 9964414, WO 0001695, WO 0012501, WO 0026208,WO 0042017, WO 0042018, WO 0042019, WO 0042020, WO 0042034, WO 0119818,WO 0130766, WO 0130777, WO 0151470, WO 02006270, WO 02066476, WO02064584 and WO 02085885.

Exemplary PDE inhibitors are shown on the following pages with the aidof their formulae:

In the above formulae there is given neither any stereochemicalinformation nor are hydrogen atoms indicated [—O is accordingly —OH, >Nis >NH or —N is NH₂]. Methyl groups, e.g. on the oxygen atoms, areindicated by lines].

Those PDE4 or PDE3/4 inhibitors are to be emphasized which are namedexpressis verbis as an example and/or claimed generically in the patentapplications or patents EP 0163965, EP 0389282, EP 0393500, EP 0435811,EP 0482302, EP 0499216, EP 0506194, EP 0510562, EP 0528922, EP 0553174,EP 0731099, WO 9319749, WO 9500516, WO 9501338, WO 9600218, WO 9603399,WO 9611690, WO 9636625, WO 9636626, WO 9723457, WO 9728131, WO 9735854,WO 9740032, WO 9743288, WO 9809946, WO 9807715, WO 9808841, WO 9821207,WO 9821208, WO 9821209, WO 9822453, WO 9831674, WO 9840382, WO 9855481,WO 9905111, WO 9905112, WO 9905113, WO 9931071, WO 9931090, WO 9947505,WO 9957115, WO 9957118, WO 9964414, WO 0001695, WO 0012501, WO 0042017,WO 0042018, WO 0042019, WO 0042020, WO 0042034, WO 0119818, WO 0130766,WO 0130777, WO 0151470 WO 02006270, WO 02066476, WO 02064584 and WO02085885 and the compounds with the following research codes: CDC-998,D4396, SCH-351591, IC-485, CC-1088 and KW-4490. Substances having goodoral availability are preferred here.

Preferred PDE4 or PDE3/4 inhibitors are3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research-Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]-benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research-Code: CI-1018], 4-(3,4-dimethoxyphenyl)-thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INNAROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine[INN:CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM],β-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research-Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenyl-carbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothiazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid [INN: CILOMILAST] and the compounds with the research codesCDC-998, SH-636, D-4396, IC-485, CC-1088 and KW-4490.

Further preferred PDE4 inhibitors are selected from the group consistingof

-   (cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3,4-Dimethoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxyphenyl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3,4-Diethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aR,8aS)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁸-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-(3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   5-{4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-5-oxo-pentanoic    acid,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid tert-butylamide,-   4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid phenylamide,-   (cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid tert-butylamide,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-2-{1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl}-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   4-(3,4-Dimethoxyphenyl)-2-[1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-naphthalen-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl-4-a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1    {2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl)-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-isopropyl-acetamide,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   1-(1    {4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-methanoyl)-4-ethyl-piperazine-2,3-dione,-   4-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-ethanoylamino)-benzoic    acid ethyl ester and-   2-{4-[(4aS,    8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-acetamide.

Particularly preferred PDE4 or PDE3/4 inhibitors are3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] and (−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a, 1b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE].

As possible histamine receptor antagonists within the meaning of thepresent invention may be mentioned, by way of example,(E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylic acid[INN: ACRIVASTINE],6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]cyclohepta-[1,2-b]-pyridin[INN: AZATADINE],4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)-phthalazinone[INN: AZELASTINE],(+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidin-1-yl]-butanoicacid [INN: BEPOTASTINE),(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazin-yl]ethoxy]-aceticacid [INN: CETIRIZINE], (+)-2-2-[(p-Chlor-alpha-methyl-alphaphenylbenzyl)oxy]-ethyl}-1-methylpyrrolidin [INN: CLEMASTINE],8-chloro-6,11-dihydro-1-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],[3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:DEXCHLORPHENIRAMINE],4′-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone [INN:EBASTINE], [2-[4-[bis(p-fluorophenyl)methyl]-1-piperazinyl]ethoxy]aceticacid [INN: EFLETIRIZINE],1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-benzimidazole[INN: EMEDASTINE],3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine [INN:EPINASTINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE],3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]propionicacid [Research Code: HSR-609],(−)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecoticacid [INN: LEVOCABASTINE],[2-[4-[(R)-p-chloro-alpha-phenyl-benzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:NORASTEMIZOLE],3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine[INN: NORTRIPTYLINE],9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [INN:PEMIROLAST],8-chloro-11-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridine[INN: RUPATADINE],1-[2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl)oxy]ethyl]hexahydro-1H-azepine[INN: SETASTINE],S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoximine [INN:SUDEXANOX],1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE], N-benzyl-N,N′-dimethyl-N-(2-pyridyl)-ethylenediamine[INN: TRIPELENAMINE] and1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:TECASTEMIZOLE].

Preferred histamine receptor antagonists are4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone [INN: AZELASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenyl-benzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE], ethyl4-(8-chloro-5,6-dihydro-1H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE] and1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE].

Particularly preferred histamine receptor antagonists are8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE] and ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE].

In the context of the present invention, unless otherwise stated, apharmaceutically acceptable derivative of an active ingredient means apharmaceutically acceptable salt or solvate (e.g. hydrate), apharmaceutically acceptable solvate of such salt, a pharmaceuticallyacceptable N-oxide or a pharmaceutically acceptable salt or solvate ofthe latter.

Suitable pharmacologically tolerable salts here are on the one hand inparticular water-soluble and water-insoluble acid addition salts withacids such as, for example, hydrochloric acid, hydrobromic acid,phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid,D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)-benzoic acid,butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid,fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid,stearic acid, toluenesulfonic acid, methanesulfonic acid or1-hydroxy-2-naphthoic acid, the acids being employed in saltpreparation—depending on whether it is a mono- or polybasic acid anddepending on which salt is desired—in an equimolar quantitative ratio orone differing therefrom. Furthermore, the active compounds mentioned canalso be present as pure enantiomers or as enantiomer mixtures in anymixing ratio.

On the other hand, salts with bases are also suitable. Examples of saltswith bases which may be mentioned are alkali metal (lithium, sodium,potassium) or calcium, aluminium, magnesium, titanium, ammonium,meglumine or guanidinium salts, where here too the bases are employed insalt preparation in an equimolar quantitative ratio or one differingtherefrom.

Certain of the active ingredients used in the present invention arecapable of existing in stereoisomeric forms. The invention encompassesall stereoisomers of the active ingredients and mixtures thereofincluding racemates. Tautomers and mixtures thereof of the activeingredients are also part of the present invention.

In accordance with the present invention, there is provided in a firstaspect a pharmaceutical composition comprising, in admixture, a firstactive ingredient which is selected from a PDE4 inhibitor, a PDE3/4inhibitor and their pharmaceutically acceptable derivatives, and asecond active ingredient which is selected from a histamine receptorantagonist and its pharmaceutically acceptable derivatives.

In a second aspect—which is an embodiment of the first aspect—there isprovided a pharmaceutical composition comprising, in admixture, a firstactive ingredient which is selected from3-Cyclopropyl-methoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], (−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxy-benzyl]-(ethylamino)-8-isopropyl-3H-purine[Research-Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research-Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INNAROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine[INN:CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM],β-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research-Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothiazolidinone[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid [INN: CILOMILAST], the compounds with the research codes CDC-998,SH-636, D4396, IC-485, CC-1088, KW-4490 and their pharmaceuticallyacceptable derivatives, and a second active ingredient which is selectedfrom (E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylicacid [INN: ACRIVASTINE],6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridin[INN: AZATADINE],4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone [INN: AZELASTINE],(+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidin-1-yl]-butanoicacid [INN: BEPOTASTINE],(plus/minus)[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE], (+)-2-{2-[(p-Chlor-alpha-methyl-alphaphenylbenzyl)oxy]ethyl}-1-methylpyrrolidin [INN: CLEMASTINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]-pyridine[INN: DESLORATADINE],[3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:DEXCHLORPHENIRAMINE],4′-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone [INN:EBASTINE], [2-[4-[bis(p-fluorophenyl)methyl]-1-piperazinyl]ethoxy]aceticacid [INN: EFLETIRIZINE],1-(2-ethoxyethyl)-2-(hexahydromethyl-1H-1,4-diazepin-1-yl)-benzimidazole[INN: EMEDASTINE],3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine [INN:EPINASTINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE],3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]propionicacid [Research Code: HSR-609],(−)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecoticacid [INN: LEVOCABASTINE],[2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE], ethyl4-(8-chloro-5,6-dihydro-11-H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:NORASTEMIZOLE],3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine[INN: NORTRIPTYLINE],9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [INN:PEMIROLAST],8-chloro-11-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridine[INN: RUPATADINE],1-[2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl)oxy]ethyl]hexahydro-1H-azepine[INN: SETASTINE],S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsuffoximine [INN:SUDEXANOX],1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE], N-benzyl-N,N′-dimethyl-N-(2-pyridyl)-ethylenediamine[INN: TRIPELENAMINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:TECASTEMIZOLE] and their pharmaceutically acceptable derivatives.

In a third aspect—which is another embodiment of the first aspect—thereis provided a pharmaceutical composition comprising, in admixture, afirst active ingredient which is selected from3-Cyclopropyl-methoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxy-benzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research-Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research-Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INNAROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-281],N-(3,5-di-chloropyridinyl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine[INN:CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM],1-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research-Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothiazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid [INN: CILOMILAST], the compounds with the research codes CDC-998,SH-636, D-4396, IC-485, CC-1088 and their pharmaceutically acceptablederivatives, and a second active ingredient which is selected from(E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylic acid[INN: ACRIVASTINE],6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridin[INN: AZATADINE],4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone [INN: AZELASTINE],(+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidin-1-yl]-butanoicacid [INN: BEPOTASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE], (+)-2-(2-[(p-Chlor-alpha-methyl-alphaphenylbenzyl)oxy]ethyl}-1-methylpyrrolidin [INN: CLEMASTINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],[3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:DEXCHLORPHENIRAMINE],4′-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone [INN:EBASTINE], [2-[4-[bis(p-fluorophenyl)methyl]-1-piperazinyl]ethoxy]aceticacid [INN: EFLETIRIZINE],1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-benzimidazole[INN: EMEDASTINE],3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine [INN:EPINASTINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE],3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]-propionicacid [Research Code: HSR-609],(−)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecoticacid [INN: LEVOCABASTINE],[2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE), ethyl4-(8-chloro-5,6-dihydro-11H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:NORASTEMIZOLE],3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine[INN: NORTRIPTYLINE],9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [INN:PEMIROLAST],8-chloro-11-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridine[INN: RUPATADINE],1-[2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl)oxy]ethyl]hexahydro-1H-azepine[INN: SETASTINE],S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoximine [INN:SUDEXANOX],I-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE], N-benzyl-N,N′-dimethyl-N-(2-pyridyl)-ethylenediamine[INN: TRIPELENAMINE] and their pharmaceutically acceptable derivatives.

In a forth aspect—which is still another embodiment of the firstaspect—there is provided a Pharmaceutical composition comprising, inadmixture, a first active ingredient which is selected from3-Cyclo-propylinethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], (−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenylybenzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE] and their pharmaceutically acceptable derivatives,and a second active ingredient which is selected from4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone[INN: AZELASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE], ethyl4-(8-chloro-5,6-dihydro-11-H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]-pyrimidin-4(3H)-one[INN: MIZOLASTINE] and1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE] and their pharmaceutically acceptable derivatives.

In the fifth aspect—which is a further embodiment of the firstaspect—there is provided a pharmaceutical composition comprising, inadmixture, a first active ingredient which is selected from(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl-2-(tetrahydrothiopyran-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-10-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Diethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aR,8aS)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-11-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-(3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,5-{4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-5-oxo-pentanoicacid,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid phenylamide,(cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-{1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl}-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-[1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-naphthalen-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)-piperidinyl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl}-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-isopropyl-acetamide,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,1-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-methanoyl)-4-ethyl-piperazine-2,3-dione,4-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenylyl-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-ethanoylamino)-benzoicacid ethyl ester,2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-acetamideand their pharmaceutically acceptable derivatives, and a second activeingredient which is selected from(E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylic acid[INN: ACRIVASTINE],6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridin[INN: AZATADINE],4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone[INN: AZELASTINE],(+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidin-1-yl]-butanoicacid [INN: BEPOTASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE], (+)-2-{2-[(p-Chlor-alpha-methyl-alphaphenylbenzyl)oxy]ethyl}1-methylpyrrolidin [INN: CLEMASTINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],[3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:DEXCHLORPHENIRAMINE]-4′-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone[INN: EBASTINE],[2-[4-[bis(p-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid [INN:EFLETIRIZINE],1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-benzimidazole[INN: EMEDASTINE],3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[_(1,5)-a]azepine [INN:EPINASTINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE],3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]propionicacid [Research Code: HSR-609],(−)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecoticacid [INN: LEVOCABASTINE],[2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:NORASTEMIZOLE],3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine[INN: NORTRIPTYLINE],9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [INN:PEMIROLAST],8-chloro-11-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridine[INN: RUPATADINE],1-[2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl)oxy]ethyl]hexahydro-1H-azepine[INN: SETASTINE],S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoximine [INN:SUDEXANOX],1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE], N-benzyl-N,N′-dimethyl-N-(2-pyridyl)ethylenediamine[INN: TRIPELENAMINE], and1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:TECASTEMIZOLE] and their pharmaceutically acceptable derivatives.

In a sixth aspect—which is still a further embodiment of the firstaspect—there is provided a pharmaceutical composition comprising, inadmixture, a first active ingredient which is selected from(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(tetrahydrothlopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Diethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aR,8aS)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-(3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,5-{4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-5-oxo-pentanoicacid,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid phenylamide,(cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenylpiperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-{1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl}-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-[1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-naphthalen-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)-piperidin-4-yl-]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl}piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-isopropyl-acetamide,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,1-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl)methanoyl)-4-ethyl-piperazine-2,3-dione,4-(2-{4[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-ethanoylamino)-benzoicacid ethyl ester,2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-acetamideand their pharmaceutically acceptable derivatives, and a second activeingredient which is selected from4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone[INN: AZELASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE],8-chloro-6,11-dihydro-1-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE] and1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1-piperidyl]-butanol[INN: TERFENADINE] and their pharmaceutically acceptable derivatives.

In a seventh aspect the invention provides a pharmaceutical productcomprising, in combination, a preparation of a first active ingredientwhich is selected from a PDE4 inhibitor, a PDE3/4 inhibitor and theirpharmaceutically acceptable derivatives, and a preparation of a secondactive Ingredient which is selected from a histamine receptor antagonistand its pharmaceutically acceptable derivatives, for simultaneous,sequential or separate use in therapy.

In a eighth aspect—which is an embodiment of the seventh aspect—theinvention provides a Pharmaceutical product comprising, In combination,a preparation of a first active ingredient which is selected from3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonyl-phenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research-Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research-Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INNAROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzylylH-indol-3-yl]-2-oxoacetamide [Research-Code: AWD-12-343],8-Amino-1,3-bis(cyclopropylmethyl)xanthine [INN:CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM],β-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research-Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothiazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid [INN: CILOMILAST], the compounds with the research codes CDC-998,SH-636, D-4396, IC-485, CC-1088, KW-4490 and their pharmaceuticallyacceptable derivatives, and a preparation of a second active ingredientwhich is selected from(E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylic acid[INN: ACRIVASTINE],6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridin[INN: AZATADINE],4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-[(2H)phthalazinone[INN: AZELASTINE],(+)-(S)-4-[4-[1-(4-chlorophenyl-1-(2-pyridyl)methoxy]piperidin-1-yl]-butanoicacid [INN: BEPOTASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE], (+)-2-(2-[(p-Chlor-alpha-methyl-alphaphenylbenzyl)oxy]ethyl}-1-methylpyrrolidin [INN: CLEMASTINE],8-chloro-6,11-dihydro-1-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],[3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:DEXCHLORPHENIRAMINE],4′-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone [INN:EBASTINE], [2-[4-[bis(p-fluorophenyl)methyl]-1-piperazinyl]ethoxy]aceticacid [INN: EFLETIRIZINE],1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-benzimidazole[INN: EMEDASTINE],3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine [INN:EPINASTINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperdino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE],3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]propionicacid [Research Code: HSR-609],(−)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecoticacid [INN: LEVOCABASTINE],[2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]-ethoxy]-aceticacid [INN: LEVOCETIRIZINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperldinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:NORASTEMIZOLE],3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine[INN: NORTRIPTYLINE],9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [INN:PEMIROLAST],8-chloro-1-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine[INN: RUPATADINE],1-[2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl)oxy]ethyl]hexahydro-1H-azepine[INN: SETASTINE],S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoximine [INN:SUDEXANOX],1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE], N-benzyl-N,N′-dimethyl-N-(2-pyridyl)-ethylenediamine[INN: TRIPELENAMINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:TECASTEMIZOLE] and their pharmaceutically acceptable derivatives, forsimultaneous, sequential or separate use in therapy.

In a ninth aspect—which is another embodiment of the seventh aspect—theinvention provides a pharmaceutical product comprising, in combination,a preparation of a first active ingredient which is selected from3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research-Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research-Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INNAROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine[INN:CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM],β-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothiazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid [INN: CILOMILAST], the compounds with the research codes CDC-998,SH-636, D-4396, IC-485, CC-1088 and their pharmaceutically acceptablederivatives, and a preparation of a second active ingredient which isselected from(E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylic acid[INN: ACRIVASTINE],6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]cyclohepta-[1,2-b]-pyridin[INN: AZATADINE],4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)-phthalazinone[INN: AZELASTINE],(+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidin-1-yl]-butanoicacid [INN: BEPOTASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE], (+)-2-{2-[(p-Chlor-alpha-methyl-alphaphenylbenzyl)oxy]-ethyl}1-methylpyrrolidin [INN: CLEMASTINE],8-chloro-6,11-dihydro-1-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],[3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:DEXCHLORPHENIRAMINE],4′-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone [INN:EBASTINE], [2-[4-[bis(p-fluorophenyl)methyl]-1-piperazinyl]ethoxy]aceticacid [INN: EFLETIRIZINE],1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-benzimidazole[INN: EMEDASTINE],3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine [INN:EPINASTINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE],3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)piperidin-1-yl]propionicacid [Research Code: HSR-609],(−)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecoticacid [INN: LEVOCABASTINE],[2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinol-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:NORASTEMIZOLE],3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine[INN: NORTRIPTYLINE],9-methyl-3-(H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [INN:PEMIROLAST],8-chloro-1-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridine[INN: RUPATADINE),1-[2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl]oxy]ethyl]hexahydro-1H-azepine[INN: SETASTINE],S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoximine [INN:SUDEXANOX],1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE], N-benzyl-N,N′-dimethyl-N-(2-pyridyl)-ethylenediamine[INN: TRIPELENAMINE] and their pharmaceutically acceptable derivatives,for simultaneous, sequential or separate use in therapy.

In a tenth aspect—which is still another embodiment of the seventhaspect—the invention provides a pharmaceutical product comprising, incombination, a preparation of a first active ingredient which isselected from3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], (−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE] and their pharmaceutically acceptable derivatives,and a preparation of a second active ingredient which is selected from4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone[INN: AZELASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-1-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE] and1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE] and their pharmaceutically acceptable derivatives,for simultaneous, sequential or separate use in therapy.

In the eleventh aspect—which is a further embodiment of the seventhaspect—the invention provides a pharmaceutical product comprising, incombination, a preparation of a first active ingredient which isselected from(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(tetrahydrothiopyran-4-yl)⁴a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Diethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(1,1-dioxohexahydro-1l⁵-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aR,8aS)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1¹⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-(3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,5-{4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-5-oxo-pentanoicacid,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid phenylamide,(cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-{1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl}4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-[1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-naphthalen-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl-3-piperidin-4-yl}4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-isopropyl-acetamide,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,1-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-methanoyl)-4-ethyl-piperazine-2,3-dione,4-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl)-ethanoylamino)-benzoicacid ethyl ester,2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-acetamideand their pharmaceutically acceptable derivatives, and a preparation ofa second active ingredient which is selected(E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylic acid[INN: ACRIVASTINE],6,11]-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]cyclohepta-[1,2-b]-pyridin[INN: AZATADINE],4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)-phthalazinone[INN: AZELASTINE],(+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidin-1-yl]-butanoicacid [INN: BEPOTASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE], (+)-2-(2-[(p-Chlor-alpha-methyl-alphaphenylbenzyl) oxy]ethyl}1-methylpyrrolidin [INN: CLEMASTINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],[3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:DEXCHLORPHENIRAMINE],4′-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone [INN:EBASTINE], [2-[4-[bis(p-fluorophenyl)methyl]-1-piperazinyl]ethoxy]aceticacid [INN: EFLETIRIZINE],1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-d]azepin-1-yl)-benzimidazole[INN: EMEDASTINE],3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine [INN:EPINASTINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE],3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]propionicacid [Research Code: HSR-609],(−)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecoticacid [INN: LEVOCABASTINE],[2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:NORASTEMIZOLE],3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine[INN: NORTRIPTYLINE],9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [INN:PEMIROLAST],8-chloro-1-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine[INN: RUPATADINE],1-[2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl)oxy]-ethyl]hexahydro-1H-azepine[INN: SETASTINE],S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoximine [INN:SUDEXANOX],1-(p-tert-butylphenyl)-4-[4-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE], N-benzyl-N,N-dimethyl-N-(2-pyridyl)-ethylenediamine[INN: TRIPELENAMINE], and1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:TECASTEMIZOLE] and their pharmaceutically acceptable derivatives, forsimultaneous, sequential or separate use in therapy.

In the twelfth aspect, which is a still further embodiment of theseventh aspect—the invention provides a pharmaceutical productcomprising, in combination, a preparation of a first active ingredientwhich is selected from(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(tetrahydrothlopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Diethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(1,1-dioxohexahydro-1l⁸-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aR,8aS)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁸-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-(3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,5-{4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-5-oxo-pentanoicacid,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid phenylamide,(cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperldinyl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2Hphthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2Hphthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-{1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl}-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-[1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-naphthalen-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl}4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-1-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl}-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,2-(4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl)-2H-isopropyl-acetamide,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,1-(1-{4-[(4aS,8aR)(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl]methanoyl)-4-ethyl-piperazine-2,3-dione,4-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-ethanoylamino)-benzoicacid ethyl ester,2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-acetamideand their pharmaceutically acceptable derivatives, and a preparation ofa second active ingredient which is selected from4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-H-azepin4-yl)-1(2H)phthalazinone (INN: AZELASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-piperazinyl]ethoxy]-aceticacid (INN: CETIRIZINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]-pyrimidin-4(3H)-one[INN: MIZOLASTINE] and1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE] and their pharmaceutically acceptable derivatives,for simultaneous, sequential or separate use in therapy.

In a thirteenth aspect, the invention provides a kit comprising apreparation of a first active ingredient which is selected from a PDE4inhibitor, a PDE3/4 inhibitor and their pharmaceutically acceptablederivatives, a preparation of a second active ingredient which isselected from a histamine receptor antagonist and its pharmaceuticallyacceptable derivatives, and instructions for the simultaneous,sequential or separate administration of the preparations to a patientin need thereof.

In a fourteenth aspect—which is an embodiment of the thirteenthaspect—the invention provides a kit comprising a preparation of a firstactive ingredient which is selected from3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research-Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research-Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-propyl-1H-purine-2,6-dione [INNAROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)H-indol-3-yl]-2-oxoacetamide [Research-Code: AWD-12-343],8-Amino-1,3-bis(cyclopropylmethyl)xanthine [INN:CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM],1-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research-Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothiazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid [INN: CILOMILAST], the compounds with the research codes CDC-998,SH-636, D-4396, IC-485, CC-1088, KW-4490 and their pharmaceuticallyacceptable derivatives, a preparation of a second active ingredientwhich is selected from(E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylic acid[INN: ACRIVASTINE],6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridin[INN: AZATADINE],4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone [INN: AZELASTINE],(+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidin-1-yl]-butanoicacid [INN: BEPOTASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE], (+)-2-{2-[(p-Chlor-alpha-methyl-alphaphenylbenzyl)oxy]ethyl}1-methylpyrrolidin [INN: CLEMASTINE],8-chloro-6,11-dihydro-1-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],[3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:DEXCHLORPHENIRAMINE],4′-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone [INN:EBASTINE], [2-[4-[bis(p-fluorophenyl)methyl]-1-piperazinyl]ethoxy]aceticacid [INN: EFLETIRIZINE],1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-benzimidazole[INN: EMEDASTINE],3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine [INN:EPINASTINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE],3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]propionicacid [Research Code: HSR-609],(−)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecoticacid [INN: LEVOCABASTINE],[2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-ylidene}-1-piperidinecarboxylate[INN: LORATADINE], 2-[N-[1-(4-fluorobenzyl)H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:NORASTEMIZOLE],3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine[INN: NORTRIPTYLINE],9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [INN:PEMIROLAST],8-chloro-11-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine[INN: RUPATADINE],1-[2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl)oxy]ethyl]hexahydro-1H-azepine[INN: SETASTINE],S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoximine [INN:SUDEXANOX],1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE], N-benzyl-N,N′-dimethyl-N-(2-pyridyl)-ethylenediamine[INN: TRIPELENAMINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:TECASTEMIZOLE] and their pharmaceutically acceptable derivatives, andinstructions for the simultaneous, sequential or separate administrationof the preparations to a patient in need thereof.

In a fifteenth aspect—which is another embodiment of the thirteenthaspect—the invention provides a kit comprising a preparation of a firstactive ingredient which is selected from3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research-Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research-Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INNAROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine[INN:CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM],β-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research-Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothiazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid [INN: CILOMILAST], the compounds with the research codes CDC-998,SH-636, D-4396, IC-485, CC-1088 and their pharmaceutically acceptablederivatives, a preparation of a second active ingredient which isselected from(E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylic acid[INN: ACRIVASTINE],6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridin[INN: AZATADINE],4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1-(2H)phthalazinone[INN: AZELASTINE],(+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidin-1-yl]-butanoicacid [INN: BEPOTASTINE], (plus/minus)[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-acetic acid[INN: CETIRIZINE], (+)-2-{2-[(p-Chlor-alpha-methyl-alphaphenylbenzyl)oxy]ethyl}1-methylpyrrolidin [INN: CLEMASTINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],[3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:DEXCHLORPHENIRAMINE],4′-tertbutyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone [INN:EBASTINE],[2-[4-[bis(p-fluorophenyl)-methyl]-1-piperazinyl]ethoxy]acetic acid[INN: EFLETIRIZINE],1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-benzimidazole[INN: EMEDASTINE],3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine [INN:EPINASTINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE],3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]propionicacid [Research Code: HSR-609],(−)-(3S,4R)-1-[cis-4-cyano(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecoticacid [INN: LEVOCABASTINE],[2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:NORASTEMIZOLE],3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine[INN: NORTRIPTYLINE],9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [INN:PEMIROLAST],8-chloro-11-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine[INN: RUPATADINE],1-[2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl)oxy]ethyl]hexahydro-1H-azepine[INN: SETASTINE],S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoximine [INN:SUDEXANOX),1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE], N-benzyl-N,N′-dimethyl-N-(2-pyridyl)-ethylenediamine[INN: TRIPELENAMINE] and their pharmaceutically acceptable derivatives,and instructions for the simultaneous, sequential or separateadministration of the preparations to a patient in need thereof.

In a sixteenth aspect—which is still another embodiment of thethirteenth aspect—the invention provides a kit comprising a preparationof a first active ingredient which is selected from3-Cyclopropyl-methoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE] and their pharmaceutically acceptable derivatives, apreparation of a second active ingredient which is selected from4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone [INN: AZELASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperdino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE] and1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-piperidyl]-butanol [INN: TERFENADINE] and their pharmaceuticallyacceptable derivatives, and instructions for the simultaneous,sequential or separate administration of the preparations to a patientin need thereof.

In the seventeenth aspect—which is a further embodiment of thethirteenth aspect—the invention provides a kit comprising a preparationof a first active ingredient which is selected from

-   (cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1    l⁵-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3,4-Dimethoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxyphenyl)-2-(tetrahydrothlopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3,4-Diethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran    yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aR,8aS)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,    5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-2-(1-Acetyl-piperidin-4-yl-4-(3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   5-(4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-5-oxo-pentanoic    acid,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid tert-butylamide,-   4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid phenylamide,-   (cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid tert-butylamide,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-2-{1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl}-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   4-(3,4-Dimethoxyphenyl)-2-[1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-naphthalen-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,    5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-{2-(4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl}-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}2H-isopropyl-acetamide,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   1-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl)methanoyl)-4-ethyl-piperazine-2,3-dione,-   4-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-ethanoylamino)-benzoic    acid ethyl ester,-   2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-acetamide    and their pharmaceutically acceptable derivatives, a preparation of    a second active ingredient which is selected from    (E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylic    acid [INN: ACRIVASTINE],    6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]cyclohepta-[1,2-b]-pyridin    [INN: AZATADINE],    4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1    (2 Hz phthalazinone [INN: AZELASTINE),    (+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidin-1-yl]-butanoic    acid [INN: BEPOTASTINE],    (plus/minus)[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-acetic    acid [INN: CETIRIZINE], (+)-2-{2-[(p-Chlor-alpha-methyl-alpha    phenylbenzyl)oxy]-ethyl}-1-methylpyrrolidin [INN: CLEMASTINE],    8-chloro-6,11-dihydro-11-(4-piperidylidene-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine    [INN: DESLORATADINE],    [3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:    DEXCHLORPHENIRAMINE],    4′-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone [INN:    EBASTINE],    [2-[4-[bis(p-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid    [INN: EFLETIRIZINE],    1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-benzimidazole    [INN: EMEDASTINE],    3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine [INN:    EPINASTINE],    (plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropic    acid [INN: FEXOFENADINE],    3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]propionic    acid [Research Code: HSR-609],    (−)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecotic    acid [INN: LEVOCABASTINE],    [2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-acetic    acid [INN: LEVOCETIRIZINE], ethyl    4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate    [INN: LORATADINE],    2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]Pyrimidin-4(3H)-one    [INN: MIZOLASTINE],    1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:    NORASTEMIZOLE],    3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine    [INN: NORTRIPTYLINE],    9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [INN:    PEMIROLAST],    8-chloro-11-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridine    [INN: RUPATADINE],    1-[2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl)oxy]ethyl]hexahydro    1H-azepine [INN: SETASTINE],    S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoximine [INN:    SUDEXANOX],    1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol    [INN: TERFENADINE],    N-benzyl-N,N′-dimethyl-N-(2-pyridyl)-ethylenediamine [INN:    TRIPELENAMINE], and    i-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:    TECASTEMIZOLE] and their pharmaceutically acceptable derivatives,    and instructions for the simultaneous, sequential or separate    administration of the preparations to a patient in need thereof.

In the eighteenth aspect—which is a still further embodiment of thethirteenth aspect—the invention provides a kit comprising a preparationof a first active ingredient which is selected from

-   (cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3,4-Dimethoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxyphenyl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3,4-Diethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁵-thiopyran-4-yl}4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(1,1-dioxohexahydro-1    la-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aR,8aS)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-(3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   5-{4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-5-oxo-pentanoic    acid,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid tert-butylamide,-   4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid phenylamide,-   (cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid tert-butylamide,-   (4aS,8aR)-443,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-2-{1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl}4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   4-(3,4-Dimethoxyphenyl-2-[1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-naphthalen-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl)-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-isopropyl-acetamide,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   1-(1-(4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-methanoyl)-4-ethyl-piperazine-2,3-dione,-   4-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-ethanoylamino)-benzoic    acid ethyl ester,-   2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-acetamide    and their pharmaceutically acceptable derivatives, a preparation of    a second active ingredient which is selected from    4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1    (2H)phthalazinone [INN: AZELASTINE],    (plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-acetic    acid [INN: CETIRIZINE],    8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo-[5,6]cyclohepta-[1,2-b]pyridine    [INN: DESLORATADINE],    (plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropic    acid [INN: FEXOFENADINE], ethyl    4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate    [INN: LORATADINE],    2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one    [INN: MIZOLASTINE] and    1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1-piperidyl]-butanol    [INN: TERFENADINE] and their pharmaceutically acceptable    derivatives, and instructions for the simultaneous, sequential or    separate administration of the preparations to a patient in need    thereof.

It has been found that the administration of active ingredientsaccording to the invention is advantageous because it results—incomparison to the administration of a single active ingredient from thePDE4 and PDE3/4 inhibitors or the histamine receptor antagonistsclass—in a reduced early allergic response and/or in a reduced lateinflammatory airway response.

The pharmaceutical composition of the present invention may be preparedby mixing the first active ingredient with the second active ingredient.Therefore, in the nineteenth aspect of the present invention, there isprovided a process for the preparation of a pharmaceutical compositionwhich comprises mixing a first active ingredient which is selected froma PDE4 inhibitor, a PDE3/4 inhibitor and their pharmacologicallyacceptable derivatives, with a second active ingredient which isselected from a histamine receptor antagonist and its pharmacologicallyacceptable derivatives.

In a twentieth aspect—which is an embodiment of the nineteenthaspect—there is provided a process for the preparation of apharmaceutical composition which comprises mixing a first activeingredient which is selected from3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research-Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research-Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INNAROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine[INN:CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM],β-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothiazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxymethoxyphenyl)cyclohexane-1-carboxylicacid [INN: CILOMILAST], the compounds with the research codes CDC-998,SH-636, D-4396, IC-485, CC-1088, KW-4490 and their pharmacologicallyacceptable derivatives, with a second active ingredient which isselected from(E)-6-[(E)-3-(1-pyrrolidinylyl-p-tolylpropenyl]-2-pyridineacrylic acid[INN: ACRIVASTINE],6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridin[INN: AZATADINE],4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone [INN: AZELASTINE],(+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidin-1-yl]-butanoicacid [INN: BEPOTASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]-ethoxy]-aceticacid [INN: CETIRIZINE], (+)-2-(2-[(p-Chlor-alpha-methyl-alphaphenylbenzyl)oxy]ethyl}-1-methylpyrrolidin [INN: CLEMASTINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]-cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],[3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:DEXCHLORPHENIRAMINE],4′-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone [INN:EBASTINE], [2-[4-[bis(p-fluorophenyl)methyl]-1-piperazinyl]ethoxy]aceticacid [INN: EFLETIRIZINE],1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)benzimidazole[INN: EMEDASTINE],3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine [INN:EPINASTINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE],3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]propionicacid [Research Code: HSR-609],(−)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecoticacid [INN: LEVOCABASTINE],[2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]4-piperldinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:NORASTEMIZOLE],3-(10,1-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine[INN: NORTRIPTYLINE],9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [INN:PEMIROLAST],8-chloro-11-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-SH-benzo[5,6]cyclohepta[1,2-b]-pyridine[INN:RUPATADINE],1-[2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl)oxy]ethyl]hexahydro-1H-azepine[INN: SETASTINE],S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoximine [INN:SUDEXANOX],1-(p-tert-butylphenyl-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE], N-benzyl-N,N′-dimethyl-N-(2-pyridyl)-ethylenediamine[INN: TRIPELENAMINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:TECASTEMIZOLE] and their pharmacologically acceptable derivatives.

In a twentyfirst aspect—which is another embodiment of the nineteenthaspect—there is provided a process for the preparation of apharmaceutical composition which comprises mixing a first activeingredient which is selected from3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research-Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepin-3(R)-yl]pyridine-4-carboxamide[Research-Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INNAROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine[INN:CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM],β-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research-Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothiazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexane-1-carboxylicacid [INN: CILOMILAST], the compounds with the research codes CDC-998,SH-636, D-4396, IC-485, CC-1088 and their pharmacologically acceptablederivatives, with a second active ingredient which is selected from(E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylic acid[INN: ACRIVASTINE],6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridin[INN: AZATADINE],4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-[(2H)phthalazinone[INN: AZELASTINE],(+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)-methoxy]piperidin-1-yl]-butanoicacid [INN: BEPOTASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE], (+)-2-{2-[(p-Chlor-alpha-methyl-alphaphenylbenzyl)oxy]ethyl}-1-methylpyrrolidin [INN: CLEMASTINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],[3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:DEXCHLORPHENIRAMINE],4′-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone [INN:EBASTINE], [2-[4-[bis(p-fluorophenyl)methyl]—piperazinyl]ethoxy]aceticacid [INN: EFLETIRIZINE],1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-benzimidazole[INN: EMEDASTINE],3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine [INN:EPINASTINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE],3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]propionicacid [Research Code: HSR-609],(−)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecoticacid [INN: LEVOCABASTINE],[2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:NORASTEMIZOLE], 3-(I0,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine[INN: NORTRIPTYLINE],9-methyl-3-(1H-tetrazol-5-yl}4H-pyrido[1,2-a]pyrimidin-4-one [INN:PEMIROLAST],8-chloro-11-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine[INN: RUPATADINE],1-[2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl)oxy]ethyl]hexahydro-1H-azepine[INN: SETASTINE],S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoximine [INN:SUDEXANOX],1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE], N-benzyl-N,N′-dimethyl-N-(2-pyridyl)-ethylenediamine[INN: TRIPELENAMINE] and their pharmacologically acceptable derivatives.

In a twentysecond aspect—which is still another embodiment of thenineteenth aspect—there is provided a process for the preparation of apharmaceutical composition which comprises mixing a first activeingredient which is selected from3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], (−)cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE] and their pharmacologically acceptable derivatives,with a second active ingredient which is selected from4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone[INN: AZELASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE],8-chloro-6,1-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE] and1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE] and their pharmacologically acceptable derivatives.

In a twentythird aspect—which is still another embodiment of thenineteenth aspect—there is provided a process for the preparation of apharmaceutical composition which comprises mixing a first activeingredient which is selected from

-   (cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(tetrahydrothlopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3,4-Dimethoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxyphenyl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3,4-Diethoxyphenyl)-2-(1,1-dioxohexahydro-11-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aR,8aS)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-11-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁸-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-2-(1-Acetyl-piperidin-4-yl-4-(3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   5-{4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-5-oxo-pentanoic    acid,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid tert-butylamide,-   4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid phenylamide,-   (cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid tert-butylamide,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-2-(1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin    yl}-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   4-(3,4-Dimethoxyphenyl)-2-[1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-naphthalen-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl}-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-isopropyl-acetamide,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   1-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-methanoyl)-4-ethyl-piperazine-2,3-dione,-   4-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-ethanoylamino)-benzoic    acid ethyl ester,-   2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-acetamide    and their pharmacologically acceptable derivatives, with a second    active ingredient which is selected from    (E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylic    acid [INN: ACRIVASTINE],    6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridin    [INN: AZATADINE],    4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone    [INN: AZELASTINE],    (+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidin-1-yl]-butanoic    acid [INN: BEPOTASTINE],    (plus/minus)[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-acetic    acid [INN: CETIRIZINE], (+)-2-(2-[(p-Chlor-alpha-methyl-alpha    phenylbenzyl)oxy]ethyl}-1-methylpyrrolidin [INN: CLEMASTINE],    8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine    [INN: DESLORATADINE],    [3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:    DEXCHLORPHENIRAMINE],    4′-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone [INN:    EBASTINE],    [2-[4-[bis(p-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid    [INN: EFLETIRIZINE],    1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-benzimidazole    [INN: EMEDASTINE],    3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine [INN:    EPINASTINE],    (plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropic    acid [INN: FEXOFENADINE],    3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]propionic    acid [Research Code: HSR-609],    (−)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecotic    acid [INN: LEVOCABASTINE],    [2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-acetic    acid [INN: LEVOCETIRIZINE], ethyl    4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate    [INN: LORATADINE],    2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one    [INN: MIZOLASTINE],    1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:    NORASTEMIZOLE],    3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine    [INN: NORTRIPTYLINE],    9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [INN:    PEMIROLAST],    8-chloro-11-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[,2-b]pyridine    [INN: RUPATADINE],    1-[2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl)oxy]ethyl]hexahydro-1H-azepine    [INN: SETASTINE],    S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoximine [INN:    SUDEXANOX],    1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol    [INN: TERFENADINE],    N-benzyl-N,N′-dimethyl-N-(2-pyridyl)-ethylenediamine [INN:    TRIPELENAMINE],    1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:    TECASTEMIZOLE] and their pharmacologically acceptable derivatives.

In a twentyfourth aspect—which is still another embodiment of thenineteenth aspect—there is provided a process for the preparation of apharmaceutical composition which comprises mixing a first activeingredient which is selected from(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1l⁸-dioxohexahydro-1l⁸-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Diethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(1,1-dioxohexahydro-1l⁸-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aR,8aS)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-(3,4-diethoxyphenyl)-4a,6,8,8a-tetrahydro-2H-phthalazin-1-one,5-{4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-5-oxo-pentanoicacid,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl]-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid phenylamide,(cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-(1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl)-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-[1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-naphthalen-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-one,(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl}-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}2H-isopropyl-acetamide,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,1-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-methanoyl)-4-ethyl-piperazine-2,3-dione,4-(2-(4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl)ethanoylamino)-benzoicacid ethyl ester,2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-acetamideand their pharmacologically acceptable derivatives, with a second activeingredient which is selected from4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone[INN: AZELASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-piperdino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one.[INN: MIZOLASTINE] and1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE] and their pharmacologically acceptable derivatives.

The first and second active ingredient may alternatively (other than inadmixture as described above) be administered simultaneously,sequentially or separately to treat respiratory diseases. By sequentialis meant that the first and second active ingredient are administeredone immediately after the other. Separately means a time difference ofadministration of up to 24 h, preferably up to 12 h.

The present invention further provides the use of a pharmaceuticalcomposition, or pharmaceutical product according to the invention in themanufacture of a medicament for the prophylaxis and/or treatment of arespiratory disease.

A further aspect of the present invention is a method for the treatmentof a respiratory disease comprising administering to a patient in needthereof (a) an effective amount of a PDE4 inhibitor, a PDE3/4 inhibitoror a pharmaceutically acceptable derivative thereof and (b) an effectiveamount of a histamine receptor antagonist or a pharmaceuticallyacceptable derivative thereof.

Respiratory diseases which may be mentioned are in particular allergen-and inflammation-induced bronchial disorders (bronchitis, obstructivebronchitis, spastic bronchitis, allergic bronchitis, allergic asthma,bronchial asthma, COPD, allergic, seasonal and perennial rhinitis),which can be treated by the combination according to the invention alsoin the sense of a long-term therapy (if desired with appropriateadjustment of the dosage of the individual components to the needs atthe time, for example needs subject to seasonally related variations).

The active ingredients may, and indeed will, as part of thepharmaceutical composition, the Pharmaceutical product or preparation,be used in admixture with one or more pharmaceutically acceptableauxiliaries and/or excipients.

Within the meaning of the present invention, “use” is preferablyunderstood as meaning the oral administration of both activeingredients. The active ingredients also can be administered as a nasalspray, an aerosol, or as an inhaled powder. Further methods ofadministration, which may be mentioned are the parenteral (e.g.intravenous) and the transdermal administration of the activeingredients.

The invention encompasses on the one hand co-administering both drugs inone delivery form such as a fixed oral combination (putting both activeingredients in one tablet), as an inhaler (putting both activeingredients in the same inhaler) or as a free oral combination (puttingboth active ingredients in two separate tablets). On the other hand itencompasses also the administration of the drugs in two differentdelivery forms such as putting the PDE4 inhibitor into tablets andpackage them with an inhaler that contains the histamine receptorantagonist, or vice versa.

The person skilled in the art is familiar on the basis of his/her expertknowledge with which excipients or auxiliaries are suitable for thedesired pharmaceutical composition, product or preparation. In additionto solvents, gel-forming agents, tablet excipients and other activecompound carriers, it is possible to use, for example, antioxidants,dispersants, emulsifiers, antifoams, flavor corrigents, preservatives,solubilizers, colorants or permeation promoters and complexing agents(e.g. cyclodextrins).

The pharmaceutical compositions or preparations according to theinvention for oral administration are preferably in the form of tablets,coated tablets, capsules, emulsions, suspensions or solutions, theactive ingredient content advantageously being between 0.1 and 95% andby appropriate choice of the excipients and the auxiliaries, it beingpossible to achieve a pharmaceutical administration form preciselytailored to the active ingredient(s) and/or to the desired onset ofaction (e.g. a sustained release form or an enteric form).

The active ingredients according to the invention are administered byinhalation preferably in the form of an aerosol; the aerosol particlesof solid, liquid or mixed composition preferably having a diameter of0.5 to 10 μm, advantageously of 2 to 6 μm.

Aerosol generation can be carried out, for example, by pressure-drivenjet atomizers or ultrasonic atomizers, but advantageously bypropellant-driven metered aerosols or propellant-free administration ofmicronized active compounds from inhalation capsules.

Depending on the inhaler system used, in addition to the activecompounds the administration forms additionally contain the requiredexcipients, such as, for example, propellants (e.g. Frigen in the caseof metered aerosols), surface-active substances, emulsifiers,stabilizers, preservatives, flavorings, fillers (e.g. lactose in thecase of powder inhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of apparatuses areavailable with which aerosols of optimum particle size can be generatedand administered, using an inhalation technique which is as right aspossible for the patient. In addition to the use of adaptors (spacers,expanders) and pear-shaped containers (e.g. Nebulator®), Volumatic®),and automatic devices emitting a puffer spray (Autohaler®), for meteredaerosols, in particular in the case of powder inhalers, a number oftechnical solutions are available (e.g. Diskhaler®, Rotadisk®,Turbohaler® or the inhaler described in European Patent Application EP 0505 321), using which an optimal administration of active compound canbe achieved.

Typical compositions for nasal delivery include those mentioned abovefor inhalation and further include non-pressurized compositions in theform of a solution or suspension in an inert vehicle such as wateroptionally in combination with conventional excipients such as buffers,anti-microbials, tonicity modifying agents and viscosity modifyingagents which may be administered by nasal pump.

Typical transdermal formulations comprise a conventional aqueous or nonaqueous vehicle, for example a cream, ointment, lotion or paste, or arein the form of a medicated plaster, patch or membrane.

For the above-mentioned therapeutic uses the dosages administered will,of course, vary with the first and second active ingredients employed,the mode of administration, the treatment desired and the disorderindicated.

However, in general, satisfactory results will be obtained when thetotal daily dosage of first active ingredient(s), the PDE4 respectivelythe PDE3/4 inhibitors, when taken oral is in the range from 1-2000 μg/kgof body weight. In the case of the particularly preferred PDE4 inhibitorROFLUMILAST, the daily dosage is in a range from 1-20 μg/kg of bodyweight. The daily dosage for the particularly preferred PDE3/4 inhibitorPUMAFENTRINE is in a range from 300-1500 μg/kg of body weight.

The total daily dosage of the second active ingredient(s), the histaminereceptor antagonists also can vary within a wide range (0.1-1500 μg/kgof body weight). In the case of the particularly preferred histaminereceptor antagonist LORATADINE, the daily dosage when taken oral is in arange from 0.1-0.5 μg/kg of body weight.

1. A pharmaceutical composition comprising, in admixture, a first activeingredient which is selected from a PDE4 inhibitor, a PDE3/4 inhibitorand their pharmaceutically acceptable derivatives, and a second activeingredient which is selected from a histamine receptor antagonist andits pharmaceutically acceptable derivatives.
 2. A pharmaceuticalcomposition according to claim 1, wherein the first and/or second activeingredient is in the form of a pharmaceutically acceptable salt,hydrate, solvate, hydrate of a salt, solvate of a salt, N-oxide, salt ofan N-oxide, hydrate of an N-oxide or solvate of an N-oxide.
 3. Apharmaceutical composition according to claim 1, which is a fixed oralcombination.
 4. A pharmaceutical composition according to claim 1, whichis a dry powder for use in a dry powder inhaler.
 5. A pharmaceuticalcomposition according to claim 1, which is an aqueous preparation fornasal administration.
 6. A pharmaceutical composition according to claim1, in which the PDE4 inhibitor, the PDE3/4 inhibitor or theirpharmaceutically acceptable derivatives and the histamine receptorantagonist or its pharmaceutically acceptable derivative is combinedwith a propellant to form a composition which is delivered using ametered dose inhaler.
 7. A pharmaceutical composition according to claim1, wherein the PDE4 inhibitor or PDE3/4 inhibitor is selected from thegroup consisting of3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine [INN: PUMAFENTRINE],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarboxamido]-pyridine-1-oxide[Research Code:SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research-Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk]-[1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INN:AROFYLLINE],3-[3(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine[INN: CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]-phenyl]-2(1H)-pyrimidone[INN: ATIZORAM],S-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research-Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothiazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid [INN: CILOMILAST] and the compounds with the research codesCDC-998, SH-636, D-4396, IC-485, CC-1088 and KW-4490, and wherein thehistamine receptor antagonist is selected from the group consisting of(E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylic acid[INN: ACRIVASTINE],6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]-cyclohepta-[1,2-b]pyridin[INN: AZATADINE],4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone[INN: AZELASTINE],(+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidin-1-yl]-butanoicacid [INN: BEPOTASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE], (+)-2-{2-[(p-Chlor-alpha-methyl-alphaphenylbenzyl)oxy]ethyl}-1-methylpyrrolidin [INN: CLEMASTINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],[3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:DEXCHLORPHENIRAMINE],4′-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone [INN:EBASTINE], [2-[4-[bis(p-fluorophenyl)methyl]-1-piperazinyl]ethoxy]aceticacid [INN: EFLETIRIZINE],1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-benzimidazole[INN: EMEDASTINE],3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine [INN:EPINASTINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE],3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]propionicacid [Research Code: HSR-609],(−)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecoticacid [INN: LEVOCABASTINE],[2-(4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:NORASTEMIZOLE],3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine[INN: NORTRIPTYLINE],9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [INN:PEMIROLAST],8-chloro-11-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine[INN: RUPATADINE],1-[2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl)oxy]ethyl]hexahydro-1H-azepine[INN: SETASTINE],S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoximine [INN:SUDEXANOX],1-(p-tert-butylphenyl)-4-[41-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE], N-benzyl-N,N′-dimethyl-N-(2-pyridyl)-ethylenediamine[INN: TRIPELENAMINE] and1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:TECASTEMIZOLE].
 8. A pharmaceutical composition according to claim 1,wherein the PDE4 inhibitor or PDE3/4 inhibitor is selected from thegroup consisting of3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarboxamido]-pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research-Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk]-[1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research-Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INN:AROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine[INN: CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM],9-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research-Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothiazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid [INN: CILOMILAST] and the compounds with the research codesCDC-998, SH-636, D-4396, IC-485 and CC-1088, and wherein the histaminereceptor antagonist is selected from the group consisting of(E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylic acid[INN: ACRIVASTINE],6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]-cyclohepta-[1,2-b]pyridin[INN: AZATADINE],4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone[INN: AZELASTINE],(+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)-methoxy]piperidin-1-yl]-butanoicacid [INN: BEPOTASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE], (+)-2-{2-[(p-Chlor-alpha-methyl-alphaphenylbenzyl)oxy]ethyl}-1-methylpyrrolidin [INN: CLEMASTINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],[3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:DEXCHLORPHENIRAMINE],41-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone [INN:EBASTINE], [2-[4-[bis(p-fluorophenyl)methyl]-1-piperazinyl]ethoxy]aceticacid [INN: EFLETIRIZINE],1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-benzimidazole[INN: EMEDASTINE],3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine [INN:EPINASTINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE],3-[4-(8-fluoro-5,11-dihydrobenz-[b]oxepino[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]-propionicacid [Research Code: HSR-609],(−)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecoticacid [INN: LEVOCABASTINE],[2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:NORASTEMIZOLE],3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine[INN: NORTRIPTYLINE],9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [INN:PEMIROLAST],8-chloro-11-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo-[5,6]cyclohepta[1,2-b]pyridine[INN: RUPATADINE],1-[2-[(p-chloro-alpha-methyl-alpha-phenyl-benzyl)oxy]ethyl]hexahydro-1H-azepine[INN: SETASTINE],S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoximine [INN:SUDEXANOX],1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE] andN-benzyl-N,N′-dimethyl-N-(2-pyridyl)-ethylenediamine [INN:TRIPELENAMINE].
 9. A pharmaceutical composition according to claim 1,wherein the PDE4 inhibitor or PDE3/4 inhibitor is selected from thegroup consisting of3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] and(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE], and wherein the histamine receptor antagonist isselected from the group consisting of4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-[(2H)phthalazinone[INN: AZELASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]aceticacid [INN: CETIRIZINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]-pyrimidin-4(3H)-one[INN: MIZOLASTINE] and1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE].
 10. A pharmaceutical composition according to claim9, wherein the PDE4 inhibitor or PDE3/4 inhibitor is selected from thegroup consisting of(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE], and the pharmaceutically acceptable salts,hydrates, solvates, hydrates of the salts, solvates of the salts,N-oxides, salts of the N-oxides, hydrates of the N-oxides or solvates ofthe N-oxides thereof.
 11. A pharmaceutical composition according toclaim 9, wherein the PDE4 inhibitor or PDE3/4 inhibitor is selected fromthe group consisting of3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the pharmaceutically acceptable salts, hydrates,solvates, hydrates of the salts, solvates of the salts, N-oxides, saltsof the N-oxides, hydrates of the N-oxides or solvates of the N-oxidesthereof.
 12. A pharmaceutical composition according to claim 1, whereinthe PDE4 inhibitor or PDE3/4 inhibitor is selected from the groupconsisting of(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Diethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aR,8aS)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-(3,4-diethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,5-{4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-5-oxo-pentanoicacid,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid phenylamide,(cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-{1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl}-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-(1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-naphthalen-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl}-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-isopropyl-acetamide,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,1-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-methanoyl)-4-ethyl-piperazine-2,3-dione,4-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-ethanoylamino)-benzoicacid ethyl ester,2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-acetamide,and wherein the histamine receptor antagonist is selected from the groupconsisting of(E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylic acid[INN: ACRIVASTINE],6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridin[INN: AZATADINE],4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-[(2H)phthalazinone[INN: AZELASTINE],(+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidin-1-yl]-butanoicacid [INN: BEPOTASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE], (+)-2-{2-[(p-Chlor-alpha-methyl-alphaphenylbenzyl)oxy]ethyl}-1-methylpyrrolidin [INN: CLEMASTINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],[3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:DEXCHLORPHENIRAMINE],41-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone [INN:EBASTINE],[2-[4-[bis(p-fluorophenyl)methyl]-1-piperazin-yl]ethoxy]acetic acid[INN: EFLETIRIZINE],1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-benzimidazole[INN: EMEDASTINE],3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine [INN:EPINASTINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE],3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino-[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]propionicacid [Research Code: HSR-609],(−)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecoticacid [INN: LEVOCABASTINE],[2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:NORASTEMIZOLE],3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine[INN: NORTRIPTYLINE],9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (INN:PEMIROLAST],8-chloro-11-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine[INN: RUPATADINE],1-[2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl)oxy]ethyl]hexahydro-1H-azepine[INN: SETASTINE],S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoximine [INN:SUDEXANOX],1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE], N-benzyl-N,N′-dimethyl-N-(2-pyridyl)-ethylenediamine[INN: TRIPELENAMINE], and1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:TECASTEMIZOLE].
 13. A pharmaceutical composition according to claim 1,wherein the PDE4 inhibitor or PDE3/4 inhibitor is selected from thegroup consisting of(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Diethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aR,8aS)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-(3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,5-{4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-5-oxo-pentanoicacid,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid phenylamide,(cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide, (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-{1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl}-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-[1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-naphthalen-1-one,(4aS,8aR)-4(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl)piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,2-{4-[(4aS,8aR)-4(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-isopropyl-acetamide,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,1-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-methanoyl)-4-ethyl-piperazine-2,3-dione,4-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-ethanoylamino)-benzoicacid ethyl ester,2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-acetamide,and wherein the histamine receptor antagonist is selected from the groupconsisting of4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-[(2H)phthalazinone[INN: AZELASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-(N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE] and1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE].
 14. A pharmaceutical composition according to claim9, wherein the histamine receptor antagonist is selected from the groupconsisting of8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE], and pharmaceutically acceptable salts, hydrates,solvates, hydrates of the salts and solvates of the salts thereof. 15.(canceled)
 16. A process for the preparation of a pharmaceuticalcomposition as defined in claim 1 which comprises mixing the firstactive ingredient with the second active ingredient.
 17. Apharmaceutical product comprising, in combination, a preparation of afirst active ingredient which is selected from a PDE4 inhibitor, aPDE3/4 inhibitor and their pharmaceutically acceptable derivatives, anda preparation of a second active ingredient which is selected from ahistamine receptor antagonist and its pharmaceutically acceptablederivatives, for simultaneous, sequential or separate use in therapy.18. A pharmaceutical product according to claim 17, wherein the firstand/or second active ingredient is in the form of a pharmaceuticallyacceptable salt, hydrate, solvate, hydrate of a salt, solvate of a salt,N-oxide, salt of an N-oxide, hydrate of an N-oxide or solvate of anN-oxide.
 19. A pharmaceutical product according to claim 17, wherein thePDE4 inhibitor or PDE3/4 inhibitor is selected from the group consistingof3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],3,5-dichloro-4[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarboxamido]-pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research-Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk]-[1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INN:AROFYLLINE],3-[3(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine[INN: CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]-phenyl]-2(1H)-pyrimidone[INN: ATIZORAM],9-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research-Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothiazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid [INN: CILOMILAST] and the compounds with the research codesCDC-998, SH-636, D-4396, IC-485, CC-1088 and KW-4490, and wherein thehistamine receptor antagonist is selected from the group consisting of(E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylic acid[INN: ACRIVASTINE],6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]-cyclohepta-[1,2-b]pyridin[INN: AZATADINE],4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone[INN: AZELASTINE],(+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidin-1-yl]-butanoicacid [INN: BEPOTASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE], (+)-2-{2-[(p-Chlor-alpha-methyl-alphaphenylbenzyl)oxy]ethyl}-1-methylpyrrolidin [INN: CLEMASTINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],[3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:DEXCHLORPHENIRAMINE],41-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone [INN:EBASTINE], [2-[4-[bis(p-fluorophenyl)methyl]-1-piperazinyl]ethoxy]aceticacid [INN: EFLETIRIZINE],1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-benzimidazole[INN: EMEDASTINE],3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine [INN:EPINASTINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE],3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]propionicacid [Research Code: HSR-609],(−)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecoticacid [INN: LEVOCABASTINE],[2-(4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:NORASTEMIZOLE],3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine[INN: NORTRIPTYLINE],9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [INN:PEMIROLAST],8-chloro-11-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine[INN: RUPATADINE],1-[2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl)oxy]ethyl]hexahydro-1H-azepine[INN: SETASTINE],S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoximine [INN:SUDEXANOX],1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE], N-benzyl-N,N′-dimethyl-N-(2-pyridyl)-ethylenediamine[INN: TRIPELENAMINE] and1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:TECASTEMIZOLE].
 20. A pharmaceutical product according to claim 17,wherein the PDE4 inhibitor or PDE3/4 inhibitor is selected from thegroup consisting of3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarboxamido]-pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research-Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk]-[1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research-Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INN:AROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine[INN: CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM],9-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research-Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothiazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid [INN: CILOMILAST] and the compounds with the research codesCDC-998, SH-636, D-4396, IC-485 and CC-1088, and wherein the histaminereceptor antagonist is selected from the group consisting of(E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylic acid[INN: ACRIVASTINE],6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]-cyclohepta-[1,2-b]pyridin[INN: AZATADINE],4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone[INN: AZELASTINE],(+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)-methoxy]piperidin-1-yl]-butanoicacid [INN: BEPOTASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE], (+)-2-{2-[(p-Chlor-alpha-methyl-alphaphenylbenzyl)oxy]ethyl}-1-methylpyrrolidin [INN: CLEMASTINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],[3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:DEXCHLORPHENIRAMINE],41-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone [INN:EBASTINE], [2-[4-[bis(p-fluorophenyl)methyl]-1-piperazinyl]ethoxy]aceticacid [INN: EFLETIRIZINE],1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-benzimidazole[INN: EMEDASTINE],3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine [INN:EPINASTINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE],3-[4-(8-fluoro-5,11-dihydrobenz-[b]oxepino[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]-propionicacid [Research Code: HSR-609],(−)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecoticacid [INN: LEVOCABASTINE],[2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:NORASTEMIZOLE],3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine[INN: NORTRIPTYLINE],9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [INN:PEMIROLAST],8-chloro-11-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo-[5,6]cyclohepta[1,2-b]pyridine[INN: RUPATADINE],1-[2-[(p-chloro-alpha-methyl-alpha-phenyl-benzyl)oxy]ethyl]hexahydro-1H-azepine[INN: SETASTINE],S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoximine [INN:SUDEXANOX],1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE] andN-benzyl-N,N′-dimethyl-N-(2-pyridyl)-ethylenediamine [INN:TRIPELENAMINE].
 21. A pharmaceutical product according to claim 17,wherein the PDE4 inhibitor or PDE3/4 inhibitor is selected from thegroup consisting of3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] and(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE], and wherein the histamine receptor antagonist isselected from the group consisting of4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone[INN: AZELASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]aceticacid [INN: CETIRIZINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]-pyrimidin-4(3H)-one[INN: MIZOLASTINE] and1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE].
 22. A pharmaceutical product according to claim 21,wherein the PDE4 inhibitor or PDE3/4 inhibitor is selected from thegroup consisting of(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE], and the pharmaceutically acceptable salts,hydrates, solvates, hydrates of the salts, solvates of the salts,N-oxides, salts of the N-oxides, hydrates of the N-oxides or solvates ofthe N-oxides thereof.
 23. A pharmaceutical product according to claim21, wherein the PDE4 inhibitor or PDE3/4 Inhibitor is selected from thegroup consisting of3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the pharmaceutically acceptable salts, hydrates,solvates, hydrates of the salts, solvates of the salts, N-oxides, saltsof the N-oxides, hydrates of the N-oxides or solvates of the N-oxidesthereof.
 24. A pharmaceutical product according to claim 17, wherein thePDE4 inhibitor or PDE3/4 inhibitor is selected from the group consistingof(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Diethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aR,8aS)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-(3,4-diethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,5-{4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-5-oxo-pentanoicacid,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid phenylamide,(cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-{1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl}-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-(1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-naphthalen-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl}-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-isopropyl-acetamide,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,1-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-methanoyl)-4-ethyl-piperazine-2,3-dione,4-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-ethanoylamino)-benzoicacid ethyl ester,2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-acetamide,and wherein the histamine receptor antagonist is selected from the groupconsisting of(E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylic acid[INN: ACRIVASTINE],6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridin[INN: AZATADINE],4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-[(2H)phthalazinone[INN: AZELASTINE],(+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidin-1-yl]-butanoicacid [INN: BEPOTASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE], (+)-2-{2-[(p-Chlor-alpha-methyl-alphaphenylbenzyl)oxy]ethyl}-1-methylpyrrolidin [INN: CLEMASTINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],[3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN:DEXCHLORPHENIRAMINE],41-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone [INN:EBASTINE],[2-[4-[bis(p-fluorophenyl)methyl]-1-piperazin-yl]ethoxy]acetic acid[INN: EFLETIRIZINE],1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-benzimidazole[INN: EMEDASTINE],3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine [INN:EPINASTINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE],3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino-[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]propionicacid [Research Code: HSR-609],(−)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecoticacid [INN: LEVOCABASTINE],[2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE],1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:NORASTEMIZOLE],3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine[INN: NORTRIPTYLINE],9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (INN:PEMIROLAST],8-chloro-11-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine[INN: RUPATADINE],1-[2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl)oxy]ethyl]hexahydro-1H-azepine[INN: SETASTINE],S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoximine [INN:SUDEXANOX],1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE], N-benzyl-N,N′-dimethyl-N-(2-pyridyl)-ethylenediamine[INN: TRIPELENAMINE], and1-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN:TECASTEMIZOLE].
 25. A pharmaceutical product according to claim 17,wherein the PDE4 inhibitor or PDE3/4 inhibitor is selected from thegroup consisting of(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Diethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶_thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aR,8aS)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-(3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,5-{4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-5-oxo-pentanoicacid,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid phenylamide,(cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide, (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-{1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl}-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-[1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-naphthalen-1-one,(4aS,8aR)-4(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)—2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl)piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,2-(4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-isopropyl-acetamide,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,1-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-methanoyl)-4-ethyl-piperazine-2,3-dione,4-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-ethanoylamino)-benzoicacid ethyl ester,2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-acetamide,and wherein the histamine receptor antagonist is selected from the groupconsisting of4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-[(2H)phthalazinone[INN: AZELASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE] and1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE].
 26. A pharmaceutical product according to claim 21,wherein the histamine receptor antagonist is selected from the groupconsisting of8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE], and pharmaceutically acceptable salts, hydrates,solvates, hydrates of the salts and solvates of the salts thereof. 27.(canceled)
 28. A kit comprising a preparation of a first activeingredient which is selected from a PDE4 inhibitor, a PDE3/4 inhibitorand their pharmaceutically acceptable derivatives, a preparation of asecond active ingredient which is selected from a histamine receptorantagonist and its pharmaceutically acceptable derivatives, andinstructions for simultaneous, sequential or separate administration tothe patient in need thereof.
 29. A kit according to claim 28, whereinthe first and/or second active ingredient is in the form of apharmaceutically acceptable salt, hydrate, solvate, hydrate of a salt,solvate of a salt, N-oxide, salt of an N-oxide, hydrate of an N-oxide orsolvate of an N-oxide or solvate of an salt or N oxide.
 30. A kitaccording to claim 28, wherein the PDE4 inhibitor or PDE3/4 inhibitor isselected from the group consisting of3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] and(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonyl-phenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE], and wherein the histamine receptor antagonist isselected from the group consisting of4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-[(2H)phthalazinone[INN: AZELASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE] and1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]butanol[INN: TERFENADINE].
 31. A kit according to claim 30, wherein the PDE4inhibitor or PDE3/4 inhibitor is selected from the group consisting of(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE], and the pharmaceutically acceptable salts,hydrates, solvates, hydrates of the salts, solvates of the salts,N-oxides, salts of the N-oxides, hydrates of the N-oxides or solvates ofthe N-oxides thereof.
 32. A kit according to claim 30, wherein the PDE4inhibitor or PDE3/4 inhibitor is selected from the group consisting of3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the pharmaceutically acceptable salts, hydrates,solvates, hydrates of the salts, solvates of the salts, N-oxides, saltsof the N-oxides, hydrates of the N-oxides or solvates of the N-oxidesthereof.
 33. A kit according to claim 28, wherein the PDE4 inhibitor orPDE3/4 inhibitor is selected from the group consisting of(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Diethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aR,8aS)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-(3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,5-{4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-5-oxo-pentanoicacid,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid phenylamide,(cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide, (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-{1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl}-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-[1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-naphthalen-1-one,(4aS,8aR)-4(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl)piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,2-{4-[(4aS,8aR)-4(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-isopropyl-acetamide,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,1-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-methanoyl)-4-ethyl-piperazine-2,3-dione,4-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-ethanoylamino)-benzoicacid ethyl ester,2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-acetamide,and wherein the histamine receptor antagonist is selected from the groupconsisting of4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-[(2H)phthalazinone[INN: AZELASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE] and1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE].
 34. A kit according to claim 30, wherein thehistamine receptor antagonist is selected from the group consisting of8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE], and pharmaceutically acceptable salts, hydrates,solvates, hydrates of the salts and solvates of the salts thereof.
 35. Amethod for the treatment of a respiratory disease comprisingadministering to a patient in need thereof (a) an effective amount of aPDE4 inhibitor, a PDE3/4 inhibitor or a pharmaceutically acceptablederivative thereof and (b) an effective amount of a histamine receptorantagonist or a pharmaceutically acceptable derivative thereof.
 36. Amethod according to claim 35, wherein the PDE4 inhibitor or PDE3/4inhibitor is selected from the group consisting of3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] and(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE].
 37. A method according to claim 35, wherein thePDE4 inhibitor or PDE3/4 inhibitor is selected from the group consistingof(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Dimethoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3,4-Diethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aR,8aS)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-(3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,5-4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-5-oxo-pentanoicacid, (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide,4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid phenylamide,(cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylicacid tert-butylamide, (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[e-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-2-{1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl}-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-[1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-naphthalen-1-one,(4aS,8aR)-4(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl)piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-isopropyl-acetamide,(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,1-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-methanoyl)-4-ethyl-piperazine-2,3-dione,4-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-ethanoylamino)-benzoicacid ethyl ester,2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-acetamide.38. A method according to claim 35, wherein the histamine receptorantagonist is selected from the group consisting of4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone[INN: AZELASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE],8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine[INN: DESLORATADINE],(plus/minus)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropicacid [INN: FEXOFENADINE], ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN: LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one[INN: MIZOLASTINE] and1-(p-tert-butylphenyl)-4-[4′-(alpha-hydroxydiphenylmethyl)-1′-piperidyl]-butanol[INN: TERFENADINE].
 39. A pharmaceutical composition according to claim1, wherein the PDE4 inhibitor or PDE3/4 inhibitor is selected from thegroup consisting of3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the pharmaceutically acceptable salts, hydrates,solvates, hydrates of the salts, solvates of the salts, N-oxides, saltsof the N-oxides, hydrates of the N-oxides or solvates of the N-oxidesthereof, and wherein the histamine receptor antagonist is selected fromthe group consisting of[2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE] and its pharmaceutically acceptablederivatives.
 40. A pharmaceutical product according to claim 17, whereinthe PDE4 inhibitor or PDE3/4 inhibitor is selected from the groupconsisting of3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the pharmaceutically acceptable salts, hydrates,solvates, hydrates of the salts, solvates of the salts, N-oxides, saltsof the N-oxides, hydrates of the N-oxides or solvates of the N-oxidesthereof, and wherein the histamine receptor antagonist is selected fromthe group consisting of[2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE] and its pharmaceutically acceptablederivatives.
 41. A pharmaceutical composition according to claim 9,wherein the PDE4 inhibitor or PDE3/4 inhibitor is selected from thegroup consisting of3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the pharmaceutically acceptable salts, hydrates,solvates, hydrates of the salts, solvates of the salts, N-oxides, saltsof the N-oxides, hydrates of the N-oxides or solvates of the N-oxidesthereof, and wherein the histamine receptor antagonist is selected fromthe group consisting of(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE] and its pharmaceutically acceptable derivatives.42. A pharmaceutical product according to claim 21, wherein the PDE4inhibitor or PDE3/4 inhibitor is selected from the group consisting of3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the pharmaceutically acceptable salts, hydrates,solvates, hydrates of the salts, solvates of the salts, N-oxides, saltsof the N-oxides, hydrates of the N-oxides or solvates of the N-oxidesthereof, and wherein the histamine receptor antagonist is selected fromthe group consisting of(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE] and its pharmaceutically acceptable derivatives.43. (canceled)
 44. A kit according to claim 28, wherein the PDE4inhibitor or PDE3/4 inhibitor is selected from the group consisting of3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the pharmaceutically acceptable salts, hydrates,solvates, hydrates of the salts, solvates of the salts, N-oxides, saltsof the N-oxides, hydrates of the N-oxides or solvates of the N-oxidesthereof, and wherein the histamine receptor antagonist is selected fromthe group consisting of[2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE] and its pharmaceutically acceptablederivatives.
 45. A kit according to claim 30, wherein the PDE4 inhibitoror PDE3/4 inhibitor is selected from the group consisting of3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the pharmaceutically acceptable salts, hydrates,solvates, hydrates of the salts, solvates of the salts, N-oxides, saltsof the N-oxides, hydrates of the N-oxides or solvates of the N-oxidesthereof, and wherein the histamine receptor antagonist is selected fromthe group consisting of(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE] and its pharmaceutically acceptable derivatives.46. A method according to claim 35, wherein the PDE4 inhibitor or PDE3/4inhibitor is selected from the group consisting of3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the pharmaceutically acceptable salts, hydrates,solvates, hydrates of the salts, solvates of the salts, N-oxides, saltsof the N-oxides, hydrates of the N-oxides or solvates of the N-oxidesthereof, and wherein the histamine receptor antagonist is selected fromthe group consisting of[2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: LEVOCETIRIZINE] and its pharmaceutically acceptablederivatives.
 47. A method according to claim 35, wherein the PDE4inhibitor or PDE3/4 inhibitor is selected from the group consisting of3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the pharmaceutically acceptable salts, hydrates,solvates, hydrates of the salts, solvates of the salts, N-oxides, saltsof the N-oxides, hydrates of the N-oxides or solvates of the N-oxidesthereof, and wherein the histamine receptor antagonist is selected fromthe group consisting of(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-aceticacid [INN: CETIRIZINE] and its pharmaceutically acceptable derivatives.